DESCRIPTION: (Applicant's abstract) Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the human cortex. Extensive studies in animals have shown that changes in GABA physiology have an important role in the origin and spread of seizure activity. The studies proposed here will use unique, non-invasive nuclear magnetic resonance spectroscopy (NMRS) to investigate GABA levels in the brain s of children with generalized, cryptogenic epilepsies who have normal anatomical neuroimaging. Recent advances in nuclear magnetic resonance spectroscopy developed in our laboratory have permitted the first non-invasive measurement of cerebral glutamate and GABA in humans. Studies of GABA synthesis and catabolism in human cortex using both proton and carbon NMRS methods will further understanding of this important neurotransmitter's role in generalized epilepsy. Our general hypothesis is that intrinsic defects of GABA physiology and metabolism result in epilepsy in these children with cryptogenic generalized epilepsy. Subjects will be identified by alterations in steady-state GABA levels as measured by proton NMRS and by both the biochemical and clinical responses to agents known to alter GABA metabolism. We will then use 13C NMRS to measure the turnover rates of GABA and precursor amino acid pools to investigate the mechanisms by which the observed alterations in GABA homeostasis occur. Studies of GABA synthesis and catabolism in human cortex using both proton and carbon NMRS methods will further understanding of this important neurotransmitter's role in generalized epilepsies in childhood. The information obtained from proposed studies will advance our understanding and ultimately improve the clinical care of children and adults with epilepsy.